Cancer can be defined by six hallmarks, including uncontrollable growth, immortality and the ability to invade other tissues. Increasing evidence suggests that a seventh feature should make this list — inflammation.
Malignant tumours are characterized by their ability to metastasize, that is, to invade anatomically distant normal tissues and to seed and grow there. During this complex and highly selective process, tumour cells leave their primary site and disseminate by various routes, such as the blood and lymph vessels. Not all cancer cells can metastasize1, because successful metastasis depends both on intrinsic properties of the tumour cells and on factors derived from the tumour microenvironment. For example, the microenvironment provides blood and lymphatic vessels in and around the tumour, an inflammatory milieu consisting of immune cells and their secretory products, and a scaffold in the form of the extracellular matrix for further growth. Writing in this issue, Kim et al.2 shed light on the unexpected molecular pathways that link inflammation in the tumour microenvironment to metastasis (page 102).
The link between inflammation and cancer is well documented3,4. Several inflammatory diseases, including inflammatory bowel disease, increase the risk of cancer. Conversely, in tumours that are epidemiologically unrelated to overt inflammatory conditions (such as breast cancer), the activation of oncogenes can orchestrate the production of inflammatory molecules and the recruitment of inflammatory cells. In the tumour microenvironment, inflammatory cells and molecules influence almost every aspect of cancer progress, including the tumour cells' ability to metastasize3. Thus, whereas there were previously six recognized hallmarks of cancer — unlimited replicative potential, self-sufficiency in growth signals, insensitivity to growth inhibitors, evasion of programmed cell death, ability to develop blood vessels, and tissue invasion and metastasis5 — cancer-related inflammation now emerges as number seven (Fig. 1).
A group of cytokine proteins, including IL-1, IL-6, TNF and RANKL, activate inflammation and are known to augment tumour cells' ability to metastasize by affecting several steps in the cells' dissemination and implantation at secondary sites3,6,7. Inflammatory cytokines lie downstream of the 'master' gene transcription factor for promoting inflammation — NF-κB — which is itself activated by them3. A major source of inflammatory cytokines in the tumour microenvironment are specialized white blood cells called macrophages. Tumour-associated macrophages assist the malignant behaviour of tumour cells, not just by producing cytokines, but also by secreting growth factors and matrix-degrading enzymes8,9,10.
Kim et al.2 explored the molecular pathways linking tumour cells, macrophages and metastasis. By purifying the components of the medium in which the tumour cells (the Lewis lung carcinoma cell line) were grown, they isolated a factor that induced cytokine production by macrophages. They identified this tumour-derived macrophage activator as versican, a protein of the extracellular matrix that is frequently upregulated in human tumours. The authors found that versican is recognized by TLR2 and TLR6, two receptor proteins that belong to a family of cellular sensors of microbially derived molecules and tissue damage. They then went on to silence versican in tumour cells by an RNA interference technique, and to use mice in which TNF and TLR were absent. On the basis of the evidence obtained, the authors propose that, in the Lewis lung carcinoma model, tumour-derived versican acts on macrophages through TLR2/TLR6, leading to the production of inflammatory cytokines, which enhance metastasis.
Kim and colleagues' observations highlight the importance of the extracellular matrix in cancer-related inflammation. The matrix acts as a depot of cytokines and growth factors, in particular vascular endothelial growth factor, which is mobilized by enzymes originating from inflammatory white blood cells and which promotes blood-vessel formation during tumour progression4,5. Moreover, during the development of cancers caused by human papillomavirus, immune cells called B cells orchestrate inflammation remotely by producing antibodies that become localized in the extracellular matrix11. What's more, a macrophage-derived extracellular-matrix protein called SPARC facilitates tumour-cell motility and metastasis12. So it seems that extracellular-matrix components are much more than a scaffold, or a substrate to be consumed during tumour-cell invasion, but instead represent a central component of cancer-related inflammation.
The present study2 offers unexpected vistas on the molecular pathways that link inflammation to acquisition of the capacity to metastasize during tumour progression. It will be essential to assess the significance of versican and other extracellular-matrix proteins in models that reflect the diversity of human cancer, for from such work innovative therapeutic strategies may follow.
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